DESCRIPTION Abstract Sleep and sleep states are fundamental not only to human life, but to every animal with a nervous system. Surprisingly, it is still not clear why they are so important. One compelling idea is that there are global shifts in the strengths of synaptic connections and excitability during sleep that act to keep synaptic function and neuronal excitability in a range where synapses and excitability of neurons can change relative to one another to allow for learning. If this does not happen, network function and behavior, whether in a worm or a human, degrade, leading ultimately to death. Such thinking about an important role of homeostatic mechanisms is moving to the fore in neuroscience, but what is needed to test hypotheses about global patterns of change in synapses and excitability is a model system and tools that allow us to monitor single synapses and neurons broadly in the living brain. We propose to develop and apply optical tools that allow us to examine patterns of scaling of synapses and excitability in the transparent zebrafish model where we can monitor these regularly and non-invasively over time during sleep and wakefulness. We will use these to directly test whether global resetting occurs during sleep. If sleep really involves such rescaling, the implications would be major, not only for a basic understanding of sleep, something that we should understand by now, but also for trying to restore functional states when sleep is impaired as a result of sleep disorders. Public Health Relevance Disorders of sleep are a major health problem, but we do not yet even understand the events that occur during sleep that make it so critical for brain function. We propose to explore global patterns of changes in synaptic strengths and neuronal excitability during sleep to test ideas that some phases of sleep are important for a broad resetting of synaptic strengths and neuronal excitability. Without sleep, a degradation of brain function ensues, leading ultimately